Allogeneic hematopoietic cell transplantation (HCT) is increasingly widely used to treat blood cancers and non-malignant blood diseases (such as hereditary anemias and immunodeficiencies), and as a platform to facilitate solid-organ transplants. However, graft-vs.-host disease (GVHD), caused by a reaction of donor immune cells against normal host tissues, is a major complication of HCT. GVHD occurs in two forms: acute and chronic. There has been substantial progress in preventing and treating the acute form of GVHD. In contrast, chronic GVHD remains a major cause of illness and death, and the major determinant of quality of life, in long-term survivors of HCT. In contrast to acute GVHD, chronic GVHD remains poorly understood on a biological level, and efforts to devise novel and effective treatments have been almost uniformly unsuccessful. Thus, the lack of effective approaches to chronic GVHD limits the application and success of allogeneic HCT. There are several factors accounting for the decades-long lack of progress against chronic GVHD. Primary among these is the lack of relevant preclinical animal models of the disease. Several mouse models of chronic GVHD have been described, but each suffers from serious limitations and fails to mirror critical aspects of human disease. Despite extensive investigation, these models have not led to the translation of novel approaches to chronic GVHD. Without a preclinical means to investigate the biology of chronic GVHD and rapidly screen treatment approaches, Phase III clinical trials of novel agents in humans have been uniformly disappointing. Thus, a desperate need exists for new and clinically relevant animal models of chronic GVHD. The dog has been used extensively as a model organism in allogeneic HCT, from the earliest days of investigation in the field. The canine model offers numerous advantages over the murine model, including greater genetic diversity, closer analogy to human immunology, and a long track record of successful translation of novel GVHD treatment approaches to the clinic. However, chronic GVHD has not been modeled or studied in the dog to this point. We have observed pathological and clinical evidence of chronic GVHD in individual dogs transplanted on various protocols at our institution. We therefore believe that chronic GVHD exists in the dog. This proposal aims to systematically develop a clinically relevant, logistically feasible, reproducible canine model of chronic GVHD. Such a model would be enormously useful in gaining biological and mechanistic insights into chronic GVHD and in rapidly testing and optimizing treatment approaches before moving to clinical trials. Ultimately, our goal is to produce a novel animal model to fill a major unmet scientific need and to facilitate research into chronic GVHD. If successful, we believe that such a model would be widely useful in studying and improving treatments for blood cancers (NCI), non-malignant blood disorders (NHLBI), and potentially solid-organ transplantation and tolerance (NIDDK, NIAID).